DESCRIPTION: (from applicant's abstract): Inflammatory pain hypersensitivity is prominent after surgery and trauma, as well in inflammatory diseases. The hypersensitivity results from changes both in primary sensory neurons and in neurons within the central nervous system. Two major complementary mechanisms have been shown to be responsible; a change in the transduction sensitivity of high threshold nociceptors, peripheral sensitization, contributed to by an increase in a tetrodotoxin-resistant sodium current, and an NMDA-receptor dependent increase in the excitability of dorsal horn neurons, central sensitization. The aim of this proposal is to examine the molecular mechanisms underlying peripheral and central sensitization by investigating if post-translational phosphorylation of two voltage-gated sodium ion channels (SNS/PN3 and SNS2/NaN) in nociceptor peripheral terminals and of NMDA receptor subunits in dorsal horn neurons, occur simultaneously during the generation of inflammatory pain hypersensitivity, when, where and the intracellular signal transduction mechanisms responsible. In addition, we will examine if this post-translational processing is augmented by later transcription dependent changes in the distribution of these effector molecules. The grant will examine several specific hypotheses. 1. Inflammation results in the phosphorylation of SNS and SNS2, two sensory neuron specific tetrodotoxin-resistant sodium channel alpha subunits and that this is mediated by inflammatory mediator-induced activation of protein kinase A and protein kinase C. 2. Inflammation results in a change in the cellular distribution of SNS and SNS2 mRNA and protein within the DRG. 3. Inflammation results in the phosphorylation of NMDA receptor subunits in the dorsal horn as a result of the activation of protein kinase A and protein kinase C by neurotransmitters and neuromodulators, and that this kinase activation alters inflammatory pain hypersensitivity. 4. The distribution and ratio of different NMDA receptor subunits in dorsal horn neurons alters after inflammation. Peripheral and central post-translational changes will occur together in clinical settings of inflammation and it is important to see them not as two separate entities but as a single general process which, although occurring in different anatomical loci and with individual molecular mechanisms, represent two manifestations of a general form of neural plasticity that contributes to the overall development of inflammatory pain hypersensitivity. Prevention of posttranslational changes may, in addition, offer new approaches for treatment of inflammatory pain hypersensitivity, a major health problem, and we need, therefore, to acquire an integrated view of these phenomena.